(S)-5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole of Formula I, which is generically known as Esomeprazole, is a Proton Pump Inhibitor. Esomeprazole Magnesium is being marketed under the Trade name NEXIUM as Delayed Release Capsules. Esomeprazole Sodium is also being marketed under the Trade name NEXIUM IV as an Intravenous Injection.
Esomeprazole is used for inhibiting gastric acid secretion in mammals and man. In a more general sense, esomeprazole is used for the treatment of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.
Several processes to prepare esomeprazole have been disclosed in the prior-art, some of which are summarized below:
U.S. Pat. No. 5,693,818 discloses a process to prepare esomeprazole by separating a diastereomeric ester of omeprazole, having either R or S configuration and dissolving each of the separated diastereomers in an alkaline solution of above pH 7 so as to hydrolyze the acyloxymethyl group from the separated diastereomers to give the optically pure enantiomers which are neutralized with a neutralizing agent which can be an acid or an ester and the pH being maintained at or above 7 throughout the process to yield esomeprazole.
U.S. Pat. No. 5,948,789 discloses a process to prepare esomeprazole, by reacting prochiral sulphide with cumene hydroperoxide in the presence of diethyl tartrate, titanium isopropoxide and amine. A disadvantage of this method is that the strict control on reaction conditions and quantities of oxidizing agents has to be maintained to avoid over oxidation of desired sulfoxide to sulfone impurity. Moreover, these methods require expensive reagents like titanium isoperoxide and diethyl tartarate.
CN 1223262 A discloses a process to prepare esomeprazole, by dissolving racemic omeprazole and (S)-(−)-[1,1′-Binaphthalene]-2,2′-diol (BINOL) in a mole ratio of 1:0.5-2 at a temperature of 60-130° C. in a solvent system such as benzene, toluene, dimethylbenzene and trimethylbenzene or acetonitrile for 12-72 h. The inclusion complex of esomeprazole and BINOL is subjected to conventional chromatographic separation to obtain optically pure esomeprazole. The reaction is carried out for longer periods, which is commercially not desirable. The maximum enantiomeric excess achieved by the above process is very low, approximately 80%.
WO 2006/094904 A1 discloses a process to prepare esomeprazole, which comprises treating the racemic mixture of omeprazole with BINOL in a molar ratio of 1:0.5-3, in a mixture of an amine and organic solvent to yield inclusion complex. The inclusion complex was treated with a hydroxide of an alkaline metal in a mixture of water and toluene to give optically pure esomeprazole. However, this process has yielded an inclusion complex of esomeprazole and BINOL with 95.7% of maximum enantiomeric excess, which requires further purification to achieve 99.7% enantiomeric excess, but this accompanied a yield loss of about 38% of inclusion complex.
WO 2007/013743 A1 discloses a process to prepare esomeprazole, which comprises treating the racemic mixture with BINOL with molar ratio of 1:0.5-0.7, in a mixture of a weak base, water and alcoholic solvent to yield the inclusion complex. The inclusion complex was treated with a hydroxide of an alkaline metal in water to give optically pure esomeprazole. However, the process yielded an inclusion complex of esomeprazole and BINOL having enantiomeric excess 96.8%, which requires further purification to achieve 99.4% enantiomeric excess, but this accompanied a yield loss of about 12% of inclusion complex.
In view of the above, it is desired to have a commercially viable process to prepare esomeprazole with high enantiomeric excess.
We have now found that by treating omeprazole with aromatic or polyaromatic phenols and optionally substituted phenols in the presence of BINOL yields esomeprazole with enhanced enantiomeric excess of greater than 98% and with a good quality. Further, the invention does not require any purification of esomeprazole-BINOL inclusion complex and carried out further reactions to yield esomeprazole with higher enantiomeric excess.
Objective
The objective of the present invention is to provide an improved process for preparing optically pure esomeprazole with good quality and purity.
In yet another objective of the present invention is to provide an improved process for preparing esomeprazole, which is simple, industrially applicable and economically viable.